POS0360 X-CHROMOSOME DOSAGE, RATHER THAN THE GONADAL SEX ITSELF, MAJORLY CONTRIBUTES TO SEX BIAS IN AUTOIMMUNITY IN HUMANS
Authors: R. Singh, E. Yen, I. Valera
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Most autoimmune diseases exhibit a profound female sex bias. Mechanisms underlying this sexual dimorphism remain unclear. We previously reported that the XX sex chromosome complement, as compared to XY, imparts greater susceptibility to autoimmune diseases such as lupus in experimental models (Smith-Bouvier D, et al, J Exp Med 2008). Gonadectomized XX female mice had more anti-DNA antibodies, autoimmune pathology, and mortality than XY female (<i>Sry</i><sup>ko</sup>) mice. Similarly, gonadectomized XX male (<i>Sry</i><sup>Tg</sup>) mice had more severe autoimmune disease than XY male (<i>Sry</i><sup>ko</sup><i>Sry</i><sup>Tg</sup>). To begin to translate these murine findings onto humans, we asked if sex chromosome dosage plays a role in predisposition to autoimmunity. <h3>Objectives</h3> To test the hypothesis that X chromosome dosage, rather than the female sex itself, imparts susceptibility to autoimmunity in humans. <h3>Methods</h3> We administered autoimmune disease and connective tissue disease questionnaires and analyzed serum autoantibody levels in males and females with sex chromosome aneuploidy including males with two X chromosomes (XX males, including Klinefelter's syndrome) and females with one X chromosome (X0 females, including Turner's syndrome) and their respective male and female controls with normal sex chromosome numbers. <h3>Results</h3> Levels of IgG anti-chromatin, anti-nucleosome and anti-histone (H2A, H2B and H3) autoantibodies were significantly higher in XX males (47,XXY; 48,XXYY, and mosaics) compared to 46,XY men. XX males, however, did not have non-specific B cell hyper-reactivity, as the levels of anti-thyroid peroxidase antibody that is associated with autoimmune thyroiditis were similar between the two groups and antibodies against intrinsic factor which are present in patients with autoimmune gastritis/pernicious anemia were reduced in XX males than in XY males. In contrast to the increased frequency of autoantibodies against systemic autoantigens in XX males vs. XY males, such autoantibodies were reduced in X0 females as compared to XX females. However, autoantibodies against organ-specific autoantigens such as thyroid and gliadin were higher in X0 females than in XX females. A preliminary analysis of clinical questionnaire revealed an increase in autoimmune conditions in XX males when compared with known population prevalence of these diseases. Preliminary immune phenotyping of peripheral blood cells conducted thus far show altered frequency and/or function of natural killer T-cells, CD8+ T cells or IL-4/IL-17 producing cells in individuals with sex chromosome aneuploidy compared to their respective controls. <h3>Conclusion</h3> These data suggest that humans with two X chromosomes as compared to those with one X chromosome, regardless of their gonadal sex, exhibit increased susceptibility to systemic autoimmunity. Preliminary evidence also suggests a differential regulation of systemic versus organ-specific autoimmunity in persons with sex chromosome aneuploidy. <h3>Reference</h3> [1]Smith-Bouvier D, Divekar A, Sasidhar M, Du S, Tiwari S, King J, Arnold A, Singh RR*, Voskuhl RR*. A role for sex chromosome complement in the female bias in autoimmune disease. <i>J Exp Med</i> 2008;205:1099-1108. *Co-corresponding author. <h3>Acknowledgements</h3> Supported in part by NIH/ NIAMS R01 grant. Thanks to Dr. Prasanth Surampudi, Christina Wang, and Ronald Swerdloff for specimens, Rita Okorogu, Jennifer Woo and Chetachi Okereke for enrollment and sample processing, and Priti Prasad, Cynthia Tran, Miguel-Angel Gutierrez, and Ramesh Halder for technical assistance. <h3>Disclosure of Interests</h3> None Declared.